Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population.

BACKGROUND: Low-grade inflammation is thought to contribute to the development of cardiovascular disease (CVD), type-2 diabetes mellitus (T2D), cancer and mortality. Biomarkers of inflammation may aid in risk prediction and enable early intervention and prevention of disease. OBJECTIVE: The aim of this study was to investigate whether plasma levels of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) are predictive of disease and mortality in the general population. DESIGN: This was an observational prospective cohort study. Cohort participants were included from June 1993 to December 1994 and followed until the end of 2006. SETTING: General adult Caucasian population. PARTICIPANTS: The MONICA10 study, a population-based cohort recruited from Copenhagen, Denmark, included 2602 individuals aged 41, 51, 61 or 71 years. MEASUREMENTS: Blood samples were analysed for suPAR levels using a commercially available enzyme-linked immunosorbent assay. Risk of cancer (n = 308), CVD (n = 301), T2D (n = 59) and mortality (n = 411) was assessed with a multivariate proportional hazards model using Cox regression. RESULTS: Elevated baseline suPAR level was associated with an increased risk of cancer, CVD, T2D and mortality during follow-up. suPAR was more strongly associated with cancer, CVD and mortality in men than in women, and in younger compared with older individuals. suPAR remained significantly associated with the risk of negative outcome after adjustment for a number of relevant risk factors including C-reactive protein levels. LIMITATION: Further validation in ethnic populations other than Caucasians is needed. CONCLUSION: The stable plasma protein suPAR may be a promising biomarker because of its independent association with incident cancer, CVD, T2D and mortality in the general population.

New risk markers may change the HeartScore risk classification significantly in one-fifth of the population.

The study aim was to determine whether urine albumin/creatinine ratio (UACR), high-sensitivity C-reactive protein (hsCRP) or N-terminal pro-brain natriuretic peptide (Nt-proBNP) added to risk prediction based on HeartScore and history of diabetes or cardiovascular disease. A Danish population sample of 2460 individuals was divided in three groups: 472 subjects receiving cardiovascular medication or having history of diabetes, prior myocardial infarction or stroke, 559 high-risk subjects with a 10-year risk of cardiovascular death above 5% as estimated by HeartScore, and 1429 low-moderate risk subjects with estimated risk below 5%. During the following 9.5 years the composite end point of cardiovascular death, non-fatal myocardial infarction or stroke (CEP) occurred in 204 subjects. CEP was predicted in all three groups by UACR (HRs: 2.1, 2.1 and 2.3 per 10-fold increase, all P<0.001) or by hsCRP (HRs: 1.9, 1.9 and 1.7 per 10-fold increase, all P<0.05), but not by Nt-proBNP (HRs: 1.1, 2.6 and 3.7 per 10-fold increase, last two P<0.001) (P<0.05 for interaction). In the low-moderate risk group, pre-specified gender adjusted (men/women) cutoff values of UACR> or =0.73/1.06 mg mmol(-1) or hsCRP> or =6.0/7.3 mg l(-1) identified a subgroup of 16% who experienced one-third of the CEPs. In the patient group, combined absence of high UACR and high Nt-proBNP> or =110/164 pg ml(-1) (men/women) identified a subgroup of 52% who experienced only 15% of the CEPs. Additional use of UACR and hsCRP in subjects with low-moderate risk and UACR and Nt-proBNP in subjects with known diabetes of cardiovascular disease changed HeartScore risk classification significantly in 19% of the population.

Impact of the metabolic syndrome on the predictive values of new risk markers in the general population.

Although the metabolic syndrome (MetS) is positively associated with high-sensitivity C-reactive protein (hsCRP), negatively associated with N-terminal pro-brain natriuretic peptide (Nt-proBNP) and inconsequently related to urine albumin/creatinine ratio (UACR) they are all associated with cardiovascular events. Therefore, we wanted to determine the influence of MetS on the predictive values of UACR, hsCRP and Nt-proBNP. On the basis of the definition of MetS by the International Diabetes Federation, a Danish population sample of 1983 apparently healthy subjects was divided into three groups: 530 subjects without any elements of MetS, 1093 subjects with some elements of MetS and 360 subjects with MetS. During the following 9.5 years the composite end point of cardiovascular death, non-fatal myocardial infarction or stroke (composite cardiovascular end point, CEP) occurred in 204 subjects. In Cox-regression analyses adjusting for age, gender and smoking, all three cardiovascular risk markers predicted CEP independently of MetS. Despite no significant interaction with MetS, high log(hsCRP) was associated with CEP primarily in subjects without any elements of MetS (hazard ratio (HR)=4.5 (1.5-14.0), P<0.01), log(Nt-proBNP) primarily in subjects with some elements of MetS (HR=3.0 (1.6-5.6), P<0.01), and logUACR independently of elements of MetS. Pre-specified gender-adjusted (men/women) cutoff values of hsCRP > or = 6.0/7.3 mg l(-1) predicted CEP in subjects without elements of MetS with positive and predictive values of 11.5 and 98%, respectively. UACR > or = 0.73/1.06 mg mmol(-1) predicted CEP in subjects with MetS with positive and predictive values of 23.5 and 93%, respectively. In apparently healthy subjects, high hsCRP was associated with CEP primarily in subjects without MetS, high Nt-proBNP in subjects with elements of MetS and UACR independently of MetS.

Evaluation of dyspnoea in a sample of elderly subjects recruited from general practice.

The objectives of this study were to investigate the cause of dyspnoea in a sample of elderly individuals and to assess the diagnostic yield of a three-step examination algorithm for the evaluation of dyspnoea paired with a cost analysis. A total of 152 subjects were examined. A predefined diagnostic approach in three steps was carried out to find the cause of dyspnoea. Step 1 included lung spirometry and ECG; step 2 included lung diffusion capacity, echocardiography, haemoglobin and thyroid function; and step 3 included cardiac magnetic resonance imaging, chest radiography and exercise test. Of 129 subjects with dyspnoea, 68 (53%) had signs of lung disease, 27 (21%) had heart disease, a total of 43 (33%) were obese, 20 (16%) were obese without other causes of dyspnoea and five (4%) had general physical deconditioning. Twelve per cent had none of the above-mentioned potential causes of dyspnoea. Steps 1, 1 + 2 and 1 + 2 + 3 revealed a cause of dyspnoea in 39%, 63%, and 73% of subjects respectively. The cost per diagnosed case at steps 2 and 3 was twice and 3.5 times the cost per diagnosed case at step 1. In this sample of elderly subjects, a potential cause of dyspnoea was identified in most cases, the most frequent being lung disease followed by heart disease and obesity. These data shed light on the diagnostic yield that can be expected from a relatively simple diagnostic approach, including the most frequent recommended initial screening tests. As expected, the incremental nature of this algorithm translated into incremental costs per diagnosis achieved.

N-terminal pro brain natriuretic peptide predicts mortality in patients with end-stage renal disease in hemodialysis.

Concentrations of N-terminal pro brain natriuretic peptide (NT-proBNP) increase in patients with heart failure and other cardiovascular (CV) diseases and are strong prognostic markers. In patients with end-stage renal disease (ESRD) in hemodialysis (HD), levels of NT-proBNP are almost always raised. In ESRD patients undergoing HD, we aimed at (i) identifying the factors that affect levels of NT-proBNP, (ii) determining the effect of HD on NT-proBNP, and (iii) determining the prognostic impact of NT-proBNP. A total of 109 patients underwent physical examination, electrocardiogram, and echocardiography. Serum NT-proBNP was measured before and after HD (Elecsys 2010). NT-proBNP levels were markedly elevated (pre-HD 4079 pg/ml, post-HD 2759 pg/ml, P<0.001). There was a strong inverse correlation between NT-proBNP and left ventricular ejection fraction (LVEF) (P=0.043), 24-h urine production (P=0.006), and K(t)/V (efficacy of dialysis) (P=0.016) and a positive correlation with left ventricular hypertrophy (LVH) (P=0.014). Patients with higher concentrations, both pre- and post-HD had an increased mortality rate compared to those with lower concentrations (P=0.007, P=0.002). We found age (P=0.009) and NT-proBNP (pre-HD P=0.007, post-HD P=0.001) predictive of death. Our findings demonstrate that CV disease in terms of LVH and reduced LVEF in addition to 24-h urine production and K(t)/V determine NT-proBNP levels. Post-HD levels of NT-proBNP were lower than pre-HD levels; both predictive of mortality.

24-h Ambulatory blood pressure in patients with ECG-determined left ventricular hypertrophy: left ventricular geometry and urinary albumin excretion-a LIFE substudy.

This study was undertaken to evaluate the relationships among left ventricular (LV) geometric patterns and urinary albumin excretion in patients with hypertension and electrocardiographic (ECG) LV hypertrophy. In 143 patients with stage II-III hypertension, 24-h ambulatory blood pressure (BP) monitoring, single urine albumin determination, and echocardiography were performed after 14 days of placebo treatment. Mean age was 68+/-7 years, 35% were women, body mass index was 28+/-5 kg/m(2), LV mass index (LVMI) was 125+/-26 g/m(2), and 24% had microalbuminuria. The mean office BP was 176+/-15/99+/-8 mmHg and the mean daytime ambulatory BP was 161+/-18/92+/-12 mmHg. Ambulatory BP, but not office BP, was higher among albuminuric compared to normoalbuminuric patients. In patients with established hypertension, daytime pulse pressure and office BP were different in the four patterns of LV geometry, with the highest pressure in those with abnormal geometry. Furthermore, microalbuminuria was more frequent in hypertensive patients with LV hypertrophy than in those with either normal geometry or concentric remodelling. White coat hypertensives (10%) showed lower LVMI and no microalbuminuria compared to patients with established hypertension. There were no differences in the prevalence of nondippers (26%) among the four LV geometric patterns or in microalbuminuria. In conclusion, increased daytime pulse pressure and office BP were associated with increased prevalence of abnormal LV geometry. Microalbuminuria was more frequent in groups with concentric and eccentric LV hypertrophy. Ambulatory BP, but not office BP, was higher in albuminuric than normoalbuminuric patients. With regard to the relationship among BP, LV geometric patterns, and urine albumin excretion in this population, 24-h ambulatory BP did not provide additional information beyond the office BP.

Diagnostic and prognostic evaluation of left ventricular systolic heart failure by plasma N-terminal pro-brain natriuretic peptide concentrations in a large sample of the general population.

OBJECTIVE: To evaluate N-terminal pro-brain natriuretic peptide (NT-proBNP) as a diagnostic and prognostic marker for systolic heart failure in the general population. DESIGN: Study participants, randomly selected to be representative of the background population, filled in a heart failure questionnaire and underwent pulse and blood pressure measurements, electrocardiography, echocardiography, and blood sampling and were followed up for a median (range) period of 805 (60-1171) days. SETTING: Participants were recruited from four randomly selected general practitioners and were examined in a Copenhagen university hospital. PATIENTS: 382 women and 290 men in four age groups (50-59 (n = 174); 60-69 (n = 204); 70-79 (n = 174); > or = 80 years (n = 120)). MAIN OUTCOME MEASURES: Value of NT-proBNP in evaluating patients with symptoms of heart failure and impaired left ventricular (LV) systolic function; prognostic value of NT-proBNP for mortality and hospital admissions. RESULTS: In 38 (5.6%) participants LV ejection fraction (LVEF) was < or = 40%. NT-proBNP identified patients with symptoms of heart failure and LVEF < or = 40% with a sensitivity of 0.92, a specificity of 0.86, positive and negative predictive values of 0.11 and 1.00, and area under the curve of 0.94. NT-proBNP was the strongest independent predictor of mortality (hazard ratio (HR) = 5.70, p < 0.0001), hospital admissions for heart failure (HR = 13.83, p < 0.0001), and other cardiac admissions (HR = 3.69, p < 0.0001). Mortality (26 v 6, p = 0.0003), heart failure admissions (18 v 2, p = 0.0002), and admissions for other cardiac causes (44 v 13, p < 0.0001) were significantly higher in patients with NT-proBNP above the study median (32.5 pmol/l). CONCLUSIONS: Measurement of NT-proBNP may be useful as a screening tool for systolic heart failure in the general population.

The influence of age, sex and other variables on the plasma level of N-terminal pro brain natriuretic peptide in a large sample of the general population.

OBJECTIVE: To identify potentially confounding variables for the interpretation of plasma N-terminal pro brain natriuretic peptide (NT-proBNP). DESIGN: Randomly selected subjects filled in a heart failure questionnaire and underwent pulse and blood pressure measurements, ECG, echocardiography, and blood sampling. SETTING: Subjects were recruited from four Copenhagen general practices located in the same urban area and were examined in a Copenhagen University Hospital. PATIENTS: 382 women and 290 men in four age groups: 50-59 years (n = 174); 60-69 years (n = 204); 70-79 years (n = 174); and > 80 years (n = 120). MAIN OUTCOME MEASURES: Associations between the plasma concentration of NT-proBNP and a range of clinical variables. RESULTS: In the undivided study sample, female sex (p < 0.0001), greater age (p < 0.0001), increasing dyspnoea (p = 0.0001), diabetes mellitus (p = 0.01), valvar heart disease (p = 0.002), low heart rate (p < 0.0001), left ventricular ejection fraction < or = 45% (p < 0.0001), abnormal ECG (p < 0.0001), high log10[plasma creatinine] (p = 0.0009), low log10[plasma glycosylated haemoglobin A1c] (p = 0.0004), and high log10[urine albumin] (p < 0.0001) were independently associated with a high plasma log10[plasma NT-proBNP] by multiple linear regression analysis. CONCLUSIONS: A single reference interval for the normal value of NT-proBNP is unlikely to suffice. There are several confounders for the interpretation of a given NT-proBNP concentration and at the very least adjustment should be made for the independent effects of age and sex.

Evaluation of impaired left ventricular ejection fraction and increased dimensions by multiple neurohumoral plasma concentrations.

BACKGROUND: A range of neurohumoral substances have been suggested as diagnostic markers in heart failure. It is, however, undetermined which marker has the greatest diagnostic potential, and whether additional information is gained by a comprehensive neurohumoral evaluation. AIMS: The purpose of the study was to compare the value of epinephrine, norepinephrine, renin activity, aldosterone (ALDO), atrial (ANP) and brain (BNP) natriuretic peptides, arginine-vasopressin and endothelin (ENDO) as markers for left ventricular (LV) dimensions and ejection fraction (LVEF) in patients with systolic heart failure. METHODS: Forty-eight patients with symptomatic heart failure were examined with blood samples and magnetic resonance imaging along with 20 age and gender-matched normal controls. RESULTS: In multiple regression analyses, BNP was the strongest independent marker for LV end-diastolic (r=0.71, P<0.0001), and end-systolic (r=0.75, P<0.0001) volumes, myocardial mass (r=0.69, P<0.0001), and LVEF (r=-0.78, P<0.0001). ANP was a supplementary independent marker for LV end-diastolic (r=0.76, P<0.0001) and end-systolic (r=0.78, P<0.0001) (ANP and BNP combined) volumes, ENDO for myocardial mass [r=0.71, P<0.0001 (ENDO/BNP)], and ALDO for LVEF [r=-0.81, P<0.0001 (ALDO/BNP)]. CONCLUSION: BNP is the strongest marker for LV dimensions and LVEF in patients with systolic heart failure. However, a comprehensive neurohumoral evaluation may add some information to the diagnosis.

[Are newer antihypertensive agents better than the older ones? Results of trials (CAPPP, STOP-2, NORDIL, INSIGHT and ALLHAT) with newer antihypertensive agents]. / Er de nye antihypertensiva bedre end de gamle? Resultater fra hypertensions-studier (CAPPP, STOP-2, NORDIL, INSIGHT og ALLHAT) med nyere medikamenter.

Until recently, no morbidity-mortality study had examined the effects of "newer" drugs, like angiotensin-converting enzyme inhibitors, calcium antagonists, and alpha-blockers compared to "old", but well-proven, thiazide diuretics, and beta-blockers in the treatment of essential hypertension. The prospective and randomised clinical trials, CAPPP, STOP-2, NORDIL, INSIGHT, and one arm of ALLHAT, with a total of about 58,000 middle-aged or elderly hypertensive patients have now been published. The primary outcome, composite cardiovascular (CV) death, cerebral stroke, and myocardial infarction, or composite fatal coronary heart disease and myocardial infarction, was the same, irrespective of the drug in all trials. Thus, prevention of CV complications depends on the lowering of blood pressure with well-tolerated medication, irrespective of class.

Antiremodeling effects on the left ventricle during beta-blockade with metoprolol in the treatment of chronic heart failure.

OBJECTIVES: The purpose of the study was to investigate the effects of beta1-blockade on left ventricular (LV) size and function for patients with chronic heart failure. BACKGROUND: Large-scale trials have shown that a marked decrease in mortality can be obtained by treatment of chronic heart failure with beta-adrenergic blocking agents. Possible mechanisms behind this effect remain yet to be fully elucidated, and previous studies have presented insignificant results regarding suspected LV antiremodeling effects. METHODS: In this randomized, placebo-controlled and double-blind substudy to the Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF), 41 patients were examined with magnetic resonance imaging three times in a six-month period, assessing LV dimensions and function. RESULTS: Decreases in both LV end-diastolic volume index (150 ml/m2 at baseline to 126 ml/m2 after six months, p = 0.007) and LV end-systolic volume index (107 ml/m2 to 81 ml/m2, p = 0.001) were found, whereas LV ejection fraction increased in the metoprolol CR/XL group (29% to 37%, p = 0.005). No significant changes were seen in the placebo group regarding these variables. Left ventricular stroke volume index remained unchanged, whereas LV mass index decreased in both groups (175 g/m2 to 160 g/m2 in the placebo group [p = 0.005] and 179 g/m2 to 164 g/m2 in the metoprolol CR/XL group [p = 0.011). CONCLUSIONS: This study is the first randomized study to demonstrate that the beta1-blocker metoprolol CR/XL has antiremodeling effects on the LV in patients with chronic heart failure and consequently provides an explanation for the highly significant decrease in mortality from worsening heart failure found in the MERIT-HF trial.

[Treatment of diabetic patients with ischaemic heart disease]. / Behandling af diabetespatienter med iskaemisk hjertesygdom.

Patients with diabetes constitute a large group among patients with ischaemic heart disease, and their risk of repeated cardiovascular events is large. Due to this, there is increasing focus on intervention against the increased risk of cardiac morbidity and mortality in patients with diabetes. Subgroup analyses of patients with diabetes from studies on patients with ischaemic heart disease show that intervention with thrombolysis, aspirin, beta blockers, ACE inhibitors and statins have similar relative benefit among patients with diabetes, but because of the greater risk in these patients, the absolute benefit is increased. In spite of this, intervention is less common among patients with diabetes, a fact that should be corrected. Direct intervention targeted at the metabolic disorder in ischaemic heart disease has only been investigated in the DIGAMI study, where glucose/insulin treatment followed by long term treatment with insulin was compared to conventional treatment. The mortality was lower in the insulin treated group after one to four years of follow up, a promising result which is currently being investigated in the DIGAMI-2 study.

[Thromboembolism following cardioversion of atrial flutter]. / Tromboemboli ved konvertering af atrieflagren.

The risk of thromboembolism following cardioversion of atrial flutter (AFL) is considered low and anticoagulant treatment (ACT) is not recommended. Nevertheless echocardiographic findings in patients with AFL and several case stories in literature suggest that the risk has been underestimated. Two cases of cerebral embolism are described after cardioversion of AFL in patients without concomitant ACT. Until further studies are available the authors recommend that patients with AFL scheduled for cardioversion receive ACT according to the recommendations for atrial fibrillation.

[Secondary prevention of ischemic heart disease. A questionnaire study and suggestions to improved cooperation between hospitals and general practice]. / Sekundaerprofylakse af iskaemisk hjertesygdom. En spørgeskemaundersøgelse og forslag til forbedret samarbejde mellem hospital og almen praksis.

The aim of the present study was to examine the extent of secondary prophylaxis in patients following hospitalization under the diagnosis of ischaemic heart (IHD). Our data were based on hospital records and questionnaires sent to patients admitted to the Cardiological Department, Frederiksberg Hospital, under the diagnosis of IHD during the first six months of 1996. One hundred and twenty-five patients were included, of these 106 answered the questionnaire. We found that overall patients were insufficiently treated with aspirin, beta-blockers and antilipidaemic agents. Measures to reduce smoking and to increase physical exercise were sparse. We concluded that secondary intervention instituted from the Cardiological Department in question was not up to generally agreed standards. Suggestions to improve secondary prophylaxis in patients with IHD are presented. The importance of increased co-operation between hospital, general practitioner and patient is emphasized. A patient-born record designed for this purpose is presented.

Local skin-fold thickness as a clinical predictor of depot size during basal rate infusion of insulin.

OBJECTIVE: To determine the influence of local adiposity on insulin depot size during CSII at basal rate. RESEARCH DESIGN AND METHODS: In 27 diabetic patients, a constant infusion of 125I-labeled Actrapid insulin was given, with U-40 insulin at a rate of 1.12 IU/h in 20 patients, and U-100 at a rate of 1 IU/h in 7 patients. After 16 h of infusion, the steady-state depot size was measured by external counting, and the local skin fold was measured with a Harpenden skin-fold caliper. RESULTS: U-40 insulin infusion resulted in a steady-state depot size of 5.1 U (2.1-10.9 U), and a corresponding skin-fold thickness of 17.8 mm (5-34 mm). A positive correlation was found between depot size and skin-fold thickness. A similar correlation was observed with U-100 insulin. CONCLUSIONS: During basal rate CSII, large variations in local skin-fold thickness create large variations in the steady-state depot size, which is partly predictable just by lifting the skin fold.